Pedro Domingues Goi

Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance

OBJECTIVE Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

Clinical staging in bipolar disorder: focus on cognition and functioning.

OBJECTIVE Clinical staging has increasingly been considered suitable for psychiatric disorders such as bipolar disorder. A staging model of bipolar disorder could help clinicians understand the mechanisms underlying the course of the illness and guide prognosis and therapy. This study aimed to investigate differences in functional status and cognitive functioning in patients in different clinical stages of bipolar disorder. METHOD Subjects who met DSM-IV criteria for bipolar disorder (n = 54) were recruited from the Bipolar Disorders Program at Hospital de Clínicas de Porto Alegre (Brazil) from October 2012 to October 2013. All patients had been in remission (score < 7 on the 17-item HDRS and the YMRS) for at least 1 month before assessment. They were classified into 4 clinical stages according to the model described by Kapczinski et al and compared to 43 healthy controls. Functional status was assessed by using the Functioning Assessment Short Test (FAST). Neuropsychological measures were performed to investigate cognitive functioning. RESULTS Significant differences in functional status were found between patients in all stages compared to controls (F = 33.014, P < .001), except for stage I (P = .104). Additionally, a very strong linear association was found between FAST scores and clinical stages, with FAST scores increasing from stage I to IV (F = 149.55, P < .001). In the bipolar group, stage I was associated with better occupational functioning than stage II (F = 48.344, P = .003). Stage IV patients experienced greater impairment in autonomy than stage III patients (F = 26.646, P = .004), and stage III patients experienced poorer autonomy than those in stage II (P = .004). With regard to cognitive measures, patients in late stages (stages III and IV) were more impaired than healthy controls (P < .001). A similar performance was found between patients in early stages (stages I and II) and healthy controls. DISCUSSION This study showed progressive functional changes from stage I to stage IV of bipolar disorder, with a greater impairment in patients in later stages of the illness. FAST scores seem to have a good discriminant ability to distinguish between patients in early versus late stages of bipolar disorder and could therefore contribute to the development of a bipolar disorder staging system.

Val66Met polymorphism and serum brain-derived neurotrophic factor in bipolar disorder: an open-label trial.

Brain‐derived neurotrophic factor (BDNF) is consistently associated with acute mood episodes in bipolar disorder, but there is a lack of longitudinal data to support this hypothesis. In this 16‐week open‐label clinical trial, we tested the predictive role of BDNF Val66Met polymorphism on serum BDNF levels and the relationship of serum BDNF and clinical response in people with bipolar disorder during an acute illness episode.

Verbal episodic memory along the course of schizophrenia and bipolar disorder: A new perspective

Impairment on episodic memory (EM) has been strongly correlated with psychiatric disorders, including schizophrenia (SZ) and bipolar disorder (BD). Morevover, the effects of course and progression of the illness on cognitive functioning have not been well established. The aim of the present study is to assess performance of episodic memory in BD and SZ according to their clinical stages. Subjects who met DSM-IV criteria for bipolar disorder (n=43) and schizophrenia (31), on euthymia or clinical remission, were recruited from the outpatients facilities at Hospital de Clínicas de Porto Alegre (Brazil). They were classified into two clinical stages (early or late for BD, and recent onset or chronic for SZ) and compared to 54 healthy controls. Episodic memory performance was assessed by means the Hopkins Verbal Learning Test-Revised (HVLT-R) that measures verbal learning and episodic memory in both disorders. Our results showed that patients in early stage of BD (EBD) performed better performance on the total immediate free recall (p<0.0001, F=12.060) as well as in delayed free recall (p<0.0001, F=13.914) compared to late stage (LBD) and SZ groups. In the ability to retain words learned, LBD and chronic (CSZ) were more impaired than other groups. Furthermore, the variation of learning (i.e, learning effects) along the 3 trials of immediate free recall was similar between groups. In conclusion, we found a cognitive decline alongside with the progression of BD whereas such impairment was evident in the early of SZ. Despite this, both groups (BD and SZ) seem to maintain the ability to learn. It emphasizes the relevance of studying new therapeutic strategies, in particular, cognitive rehabilitation/remediation techniques as promissory treatment for psychiatric patients, even in those with moderate disabilities.

Bipolar disorder affects behavior and social skills on the Internet.

Background Bipolar disorder (BD) is a significant cause of functional, cognitive, and social impairment. However, classic studies of functioning and social skills have not investigated how BD may impact behavior on the Internet. Given that the digital age has been changing the way people communicate, this study aims to investigate the pattern of Internet use in patients with BD. Methods This cross-sectional study assessed 30 patients with BD I or II and 30 matched controls. Patients were not in an acute mood episode, according to DSM-IV. A standard protocol examined sociodemographic variables and social behavior on the Internet, assessed by Facebook number of friends (FBN) and lifetime estimated number of offline contacts (social network number, SNN). Results SNN (p<0.001) and FBN (p = 0.036) of patients with BD were significantly lower than those of controls. Also, variables related with Internet use were significantly lower in patients, e.g., close contacts on Facebook (p = 0.021), Internet experience (p = 0.020), and knowledge of terms associated with social networking sites (p = 0.042). Also, patients showed lower rates of the expected pattern of Internet use (based on their age generation), including a poorer knowledge of SNS (p = 0.018) and a lower frequency of Internet use (p = 0.010). Discussion This study suggests that patients with BD show smaller social networks both in real-world settings and on the Internet. Also, patients tend to use the Internet and social networking sites less frequently and show a poorer knowledge of Internet and social media than healthy controls, below the expected for their generation. These significant differences between patients and controls suggest that the effects of BD on social relationships and functioning extend to electronic media.

Verbal memory impairment in healthy siblings of patients with schizophrenia

Cognitive deficits have been recognized as a core feature of schizophrenia (SZ) and are present in most patients. Verbal memory (VM), working memory (WM), and executive function (EF) are domains commonly impaired in patients with SZ. These latter domains have been related to the genetic risk of the disorder characterizing as possible endophenotypes. In order to study neurocognitive endophenotypes in a Brazilian population with elevated genetic risks to develop SZ, we measured VM (Hopkins Verbal Learning Test Revised), WM (Letter-Number Sequencing and Digit Span) and EF (Stroop Test) in 90 subjects (45 unaffected siblings of patients with SZ and 45 matched healthy controls). No differences were found in EF and WM (Letter-Number Sequencing and Digit Span). However, in VM, siblings of patients performed worse than controls on the immediate recall and delayed recall. Our results suggest that VM impairment could be considered an endophenotype of SZ.

Pharmacological treatment and staging in bipolar disorder: evidence from clinical practice

OBJECTIVES Staging models for medical diseases are widely used to guide treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is among the most disabling disorders in medicine. The staging model proposed by Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to evaluate pharmacological maintenance treatment across these stages in patients with BD. METHODS One hundred and twenty-nine subjects who met DSM-IV criteria for BD were recruited from the Bipolar Disorders Program at Hospital de Clínicas de Porto Alegre, Brazil. All patients were in remission. The subjects were classified according to the staging model: 31 subjects were classified as stage I, 44 as stage II, 31 as stage III, and 23 as stage IV. RESULTS Patterns of pharmacological treatment differed among the four stages (p = 0.001). Monotherapy was more frequent in stage I, and two-drug combinations in stage II. Patients at stages III and IV needed three or more medications or clozapine. Impairment in functional status (Functioning Assessment Short Test [FAST] scale scores) correlated positively with the number of medications prescribed. CONCLUSIONS This study demonstrated differences in pharmacological treatment in patients with stable BD depending on disease stage. Treatment response can change with progression of BD. Clinical guidelines could consider the staging model to guide treatment effectiveness.

Treatment delay is associated with more episodes and more severe illness staging progression in patients with bipolar disorder.

Onset of bipolar disorder (BD) in childhood is common and often associated with extraordinarily long delays to specific treatment. Perlis et al. in the STEP-BD study found that 66% of their cohort had onset in childhood or adolescence (until the age of 18) (Perlis et al., 2004). They also reported that early onset was associated with more comorbid substance abuse and anxiety, greater number of mood episodes and suicide attempts. To corroborate this idea, Post et al. reported that treatment delay was associated with a persistent adverse course of illness rated prospectively in adults (Post et al., 2010). The staging model proposed by Kapczinski for BD assumes 1 latent and 4 clinical stages, based on the biological, functional and clinical neuroprogression (Kapczinski et al., 2009). According to this model, in stage I, patients have well-defined periods of euthymia and no cognitive impairment; in stage II, they have interepisodic symptoms due to comorbidities and transient cognitive impairment; in stage III, marked cognitive and functional impairment; and in stage IV, cognitive and functional impairment prevents autonomous living. Adverse courses of illness presumably show more rapid neuroprogression, and it is possible that patients with treatment delay have more severe illness staging classification. The aim of this study is to examine the association between time to the first correct treatment for BD, measured in years, and the clinical stages among patients with BD. Two hundred forty-three outpatients with BD from Hospital de Clínicas de Porto Alegre, Brazil, were screened for this study. Out of those, 127 met inclusion criteria: (1) Age 418 years; (2) fulfilling DSM-IV-TR criteria for BD Type I, according to the Structured Clinical Interview for DSM-IV-TR; (3) meeting remission criteria (Young Mania Rating Scale and the 17 items Hamilton Depression Scale both less than 7 points in the last month); (4) absence of comorbid mental retardation/severe intellectual disabilities; (5) absence of severe unstable medical comorbidities; and (6) being able to comprehend and give informed consent. Sociodemographic and clinic variables were evaluated by the research protocol. Disease onset was defined as the first DSM-IV-TR mood episode. Classification in the 4 clinical stages was performed by experienced psychiatrists using a semistructured interview assessing clinical, social, laboral and functional history. Data was checked with family and the assistant psychiatrist (Rosa et al., 2014). The local ethics committee approved the study and all participants gave written informed consent. The sample consisted in 31 stage I patients, 43 stage II, 31 stage III and 22 stage IV, 72% of them female. The mean age was 44.6 (SD1⁄412.8), and mean age of illness onset was 28.7 (SD1⁄412.5) years. Thirty-two percent of patients had illness onset in childhood or adolescence. Sample was stratified regarding previous mood episodes in three groups (o5 episodes, 5–10 episodes, and 410 episodes). Treatment delay in years was different between stratification groups (Anova F1⁄44.399, df1⁄42, p1⁄40.014), greater in the 410 episodes group compared to the o5 episodes group (Tukey post-hoc, p1⁄40.010). Anova test also showed differences in the magnitude of treatment delay among BD clinical stages (F1⁄42.806, df1⁄43, p1⁄40.043). Tukey post-hoc analyses showed less delay in treatment in Stage I, compared to later stages (Io II1⁄4 III1⁄4 IV, p1⁄40.041). These results converge with previous evidence that treatment delay in BD is associated with episode recurrence and a more adverse course of illness. Our study amplifies existing evidence towards the idea of staging, showing that earlier detection and more effective early intervention could help preventing disorder progression. Early detection and intervention could also maintain patients living with minimum or no cognitive and functional impairments. A longer duration of untreated BD is also correlated with the number of medical comorbidities, such as hypertension and metabolic disorders (Maina et al., 2013); reinforcing the idea of mood episode toxicity (Kapczinski et al., 2010, 2011). Comorbidities increase disease burden, lead to a worse course of illness and, finally, accelerates neuroprogression to later stages (Kapczinski et al., 2009; Maina et al., 2013). Studies with longitudinal designs and with a broader investigation of risk factors for progression to later stages of BD are of vital importance. Nonetheless, our results have implications for understanding neuroprogression hypothesis of mood disorders and help the argument for examining the mood symptoms impact on neurobiological and clinical outcomes.

Frequency of brain tissue donation for research after suicide

Objectives: To describe the frequency of brain tissue donation for research purposes by families of individuals that committed suicide. Methods: All requests for brain tissue donation to a brain biorepository made to the families of individuals aged 18-60 years who had committed suicide between March 2014 and February 2016 were included. Cases presenting with brain damage due to acute trauma were excluded. Results: Fifty-six cases of suicide were reported. Of these, 24 fulfilled the exclusion criteria, and 11 others were excluded because no next of kin was found to provide informed consent. Of the 21 remaining cases, brain tissue donation was authorized in nine (tissue fragments in seven and the entire organ in two). Conclusions: Donation of brain tissue from suicide cases for research purposes is feasible. The acceptance rate of 42.8% in our sample is in accordance with international data on such donations, and similar to rates reported for neurodegenerative diseases.

Accumbens volumes are reduced among crack-cocaine users

The brain reward system is known to be the neuroanatomical basis of addictive behaviors. Systemic, cognitive and functional consequences of crack-cocaine addiction are clinically evident, but the neuroanatomical underpinnigs are not yet well understood. We aim to assess the neuroanatomical differences between crack-cocaine patients and paired healthy controls. Fifteen crack-cocaine patients recently discharged from the Addiction Unit of the Hospital de Clínicas de Porto Alegre and fifteen controls matched for gender, age, education and handedness were scanned using a Philips Achieva 1.5T MRI equipment. All subjects had negative positive tests at admission and patients had at least 15days of detoxification. Active neurologic, inflammatory, cardiovascular or systemic comorbidities were excluded. Subcortical structure volumes were determined using Freesurfer v5.1. Controls had greater volumes in the left accumbens (t=3.604, df=28, p=0.001) compared to patients. Right accumbens volumes were also greater in controls (t=2.098, df=28, p=0.045). Groups did not differ regarding intracranial volumes (p=0.514). This preliminary and innovative data on crack-cocaine dependence suggests that there is a volumetric reduction of the accumbens, a region that has a significant role in motivation, pleasure, reward and reinforcement learning, and it could play a central role in the pathophysiology of this drug addiction. Therefore, these findings may contribute to understand some behavioral and cognitive deficits in this population.